Our goal is to develop new, broad-spectrum anti-viral agents for treating viral infections caused by hostile dissemination of viral pathogens. The new agents act by targeting normally-internal phospholipids (e.g. phosphatidylserine, PS) that become exposed on the surface of virally-infected cells. Exposure of these phospholipids on infected host cells appears to be necessary for viral maturation or egress. We have raised monoclonal antibodies to PS and other anionic phospholipids that block the spread of several viruses to uninfected cells in vitro, essentially completely. The viruses we have tested thus far include an arenavirus (Pichinde virus), a paramyxovirus (respiratory syncytial virus) and a herpes virus (cytomegalovirus). The phospholipids that they recognize have the same structure and cellular distribution in different mammalian species, simplifying the transition from experimental animals into humans. The antibodies are not toxic to mice, even when administered in high doses for prolonged periods of time. One of the antibodies has been converted into a human-mouse chimeric antibody (ch3G4) and is being produced in a GMP facility by a commercial partner in anticipation of human use. We propose to develop ch3G4 first for treating Lassa fever. Development studies will be conducted in a guinea pig model, which uses the arenavirus, Pichinde, to mimic Lassa fever in humans. The animal model will enable us to safely investigate the mechanism of the anti-viral effect and to establish basic efficacy, safety and pharmacokinetic parameters. Key findings will then be validated for Lassa fever virus itself and with other arenaviruses that cause hemorrhagic fevers in a BSL-4 containment facility at UTMB Center for Biodefense, Galveston. The information generated by these studies may also extend to other viruses that could be used for bioterrorism purposes.